Interleukin (IL)-17 plays a key role in anti- bacterial and anti-fungal immunity. In acute infections, a rapid IL-17 response must be induced quickly without prior antigen exposure, and ?? T cells have been identified as the major initial IL-17 producers. In particular, some ?? T cells make IL-17 within hours after an immune challenge. These cells appear to acquire the ability to respond to IL-1 and IL-23 and to make IL-17 naturally in nave animals. They are known as the natural T??17 (nT??17) cells. The critical rle of nT??17 cells in host immune defense is well documented. But, the molecular cues that drive this response remain elusive. The rapidity of the nT??17 response, and the apparent lack of explicit T cell receptor (TCR) engagement for its induction have led to the view that this is a cytokine (IL-1, IL-23)-mediated response. However, pharmacological inhibition or genetic defects in TCR signaling drastically reduces the nT??17 response and/or their presence, suggesting that antigen recognition is important to their function. In addition, the appearance of nT??17 cells in the gut depends on the presence of specific commensal bacteria. But, the molecular cues for this process in not clear. Moreover, although the importance of nT??17 cells in immune defense is well demonstrated in mouse models of infection, whether there is a human counterpart is unclear. This application seeks to address these issues. This study should shed new light on the molecular cues that drive nT??17 cell function, which is important in initial immune defense and has a profound influence on the development of the inflammatory response. It may also have important implications in human immune response to infectious diseases.